The present application relates to the field of diabetes mellitus (DM). In particular, methods for determining separately or concurrently with a simple, minimally invasive test the presence of tissue insulin resistance and/or the adequacy of pancreatic beta-cell response or compensation in an individual and therefore the individual's susceptibility to developing DM type 2 (DM2) or progressing to more advanced DM2, are described.
The current pathogenic model of type 2 diabetes mellitus (DM2) invokes a two-step process: (1) Insulin resistance (i.e., reduced sensitivity of tissues to the actions of insulin); and (2) Pancreatic beta-cell failure (i.e., insufficient secretion of insulin to compensate for insulin resistance). This model explains numerous empirical observations in the field of DM including:                a) The high predictive power of gestational diabetes (GDM) for subsequent permanent DM2. Pregnancy causes insulin resistance in all women (due to the high levels of progesterone). The inability to increase pancreatic insulin secretion for three months to compensate for insulin resistance, manifested by subsequent development of GDM, therefore predicts failure of the pancreas to compensate and the ultimate development of DM2 when long-standing insulin resistance occurs associated with obesity, aging and sedentary life-style.        b) The observation that only 25-30% of obese (insulin resistant) people will develop DM2. The remaining individuals maintain compensated (hyperinsulinemic) insulin resistance and do not develop DM2. Thus, two lesions are required for the development of DM2 (insulin resistance and pancreatic insufficiency).        c) The natural history of blood insulin concentrations in the progression of obesity to DM2. Insulin concentrations initially rise above normal levels, then fall to normal or low levels, as DM2 emerges.        d) The observation that insulin-sensitizing interventions can prevent progression of pre-diabetes to diabetes. Reducing insulin resistance by exercise or metformin therapy has been shown to improve pancreatic insulin secretion and to prevent progression to DM2.        e) The observation that progression of long-standing DM2, in the United Kingdom Prospective Diabetes Study (UKPDS), for example, involves mainly worsening of beta-cell function, not worsening of insulin resistance. This study showed that patients with long-standing DM2 require more and more drugs to maintain good diabetic control over time, primarily because of worsening insulin secretion, not changes in insulin resistance.Implications for Diagnostic Monitoring and Drug Testing        
Accordingly, full characterization of susceptibility to DM2 or progression along the pathway to DM2 requires information about those two elements or dimensions (insulin resistance and pancreatic beta-cell compensation) involved in the pathogenesis of DM2.
Bergman and others have proposed tests to assess both dimensions. The Frequently Sampled IV Glucose Tolerance Test (FS IVGTT) measures the insulin sensitivity index (ISI) and the acute insulin response to glucose (AIRG), and calculates the adequacy of beta-cell response from these two measured parameters. This method has been extensively used in humans at risk for developing diabetes and has supported the model (Kahn et al, Wyeth et al, see references infra) shown in FIG. 1. The central concept is that a hyperbolic relationship exists between tissue insulin resistance and pancreatic insulin secretion. As insulin sensitivity (ISI) falls, AIRG should rise, so that the product of ISI×AIRG (termed the disposition index or DI) should remain constant (FIG. 1, black line). DI therefore represents a calculated measure of the adequacy of pancreatic compensation to insulin resistance, or an indirect measure of beta-cell sufficiency in the face of insulin resistance. Accordingly, individuals who fail to maintain constancy of DI as ISI falls (gray line in FIG. 1)—i.e., do not fall on the expected hyperbolic curve of ISI vs. AIRG (black line in FIG. 1)—are considered to be showing evidence of pancreatic beta-cell insufficiency.
Investigators have shown that such individuals, whose DI is not maintained in the face of reduced ISI, indeed appear to be at higher risk of developing DM2. Moreover, failure to maintain constant DI is a heritable trait within families at different risks for DM2. DI has therefore been proposed as a means of identifying those insulin resistant individuals who are highly susceptible to developing DM2.
The FS IVGTT is problematic as a test, however, and is much too invasive and complicated to be used in clinical diagnostics, for the following reasons: (1) The placement of an intravenous line is required; (2) multiple blood draws according to an exactly timed protocol are required (e.g., every 1-2 minutes for 20 minutes, then follow-ups through 2 hours); (3) sterile iv glucose must be injected; (4) a drug (tolbutamide) must be injected iv at exactly 20 minutes after iv glucose (carrying some risk and the need for medical supervision) (5) multiple laboratory tests for glucose and insulin concentrations must be sent; and (6) a computerized calculation must be carried out on the data generated. The FS IVGTT is therefore labor-intensive, invasive, costly, difficult to interpret, and to some extent a risky procedure.
Other methods are available for estimating or measuring insulin resistance. These include hyperinsulinemic glucose clamps (considered the “gold standard” for insulin resistance), and the similar steady-state plasma glucose (SSPG) method, the homeostatic model assessment (HOMA), and simple measurement of plasma insulin concentrations. None of these methods can give information about pancreatic beta-cell function or the adequacy of beta-cell compensation for insulin resistance, however. Indeed, the glucose clamp and SSPG methods explicitly control blood insulin to remove the potential confounding influence of pancreatic insulin secretion. There currently are no practically usable tests for measuring or estimating the adequacy of pancreatic beta-cell response to insulin resistance.
It should be apparent that the absence of a simple, practically usable test for identifying individuals who are both insulin resistant and who are exhibiting insufficient pancreatic beta-cell response—and are therefore highly susceptible to developing diabetes or to worsening of existing diabetes—is a major limitation in the field of diabetes. The present emergence in diabetic therapeutic research of agents that may increase pancreatic beta-cell proliferation and function makes the absence of an outcome metric for beta-cell adaptive function particularly critical.